This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. One of the most remarkable mechanical devices that Nature has engineered consists of two small folds of tissue called vocal folds, which are responsible for the production of a great variety of sounds when vibrated by the tracheal air-stream. Under normal conditions, vocal folds can sustain up to 30% strain at frequencies of 100 to 1000 Hz. However, excessive mechanical stresses and deleterious pathological conditions can cause damage to this delicate system, resulting in a wide spectrum of vocal fold disorders. To date, optimal treatment for vocal fold disorders has not yet been realized, and tissue engineering methods hold promise for the regeneration of functional vocal folds. However, the unique biochemical composition, structural organization, and viscoelastic properties of vocal folds have significantly complicated tissue engineering efforts that utilize traditional polymeric biomaterials. In this new collaborative effort that integrates the unique expertise of junior and early-career faculty, we will produce novel bioactive elastomers that can be used as conducive scaffolds for vocal fold tissue engineering. These biomaterials will capture the molecular architecture and mechanical characteristics of natural elastic proteins (elastin and resilin);given the different physicochemical properties of these two proteins, employing both will offer a comprehensive approach for tuning morphological, mechanical and biological properties in the new materials. The elastin mimetic hybrid polymers (EMHP) will comprise a multiblock structure with alternating hydrophobic, elastic synthetic domains and hydrophilic, peptide-based cross-linking domains. The synthetic blocks are expected to show rubber-like elasticity that will functionally mimic the properties of the elastic domains of elastin, while the peptide domains will serve both structural and biological function. In addition, resilin-based modular polypeptides (RBMP) will be produced with multiple repeats of unique functional modules including resilin-based peptide domains, heparin-binding peptides, cell-adhesive peptides, and MMP-sensitive domains in order to produce materials that present useful biological cues while exhibiting high resilience at high frequencies. Our synthetic strategies will exploit the established versatility of synthetic polymer chemistry and solid state peptide synthesis, as well as new orthogonal organic chemistry developed in this COBRE proposal. Chemical methods employing both natural and non-natural amino acids will be used to crosslink EMHP and RBMP to systematically match mechanical properties to those of the natural vocal fold lamina propria. With the aid of clinical collaborators at Christiana Care and the A.I. duPont Hospital for Children, the bioactive elastomers will be evaluated for their ability to promote vocal fold cell proliferation, angiogenesis, and ECM production. These new materials and approaches offer promising routes to ultimately engineering functional vocal fold lamina propria via a combination of viable cells, elastic scaffolds, biological factors and mechanical stimulation.